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Nutrition Research Reviews (2011), 24, 206–227 doi:10.

1017/S0954422411000114
q The Authors 2011

Human health effects of conjugated linoleic acid from milk and supplements

Tracy A. McCrorie1*, Edel M. Keaveney1, Julie M. W. Wallace1, Nino Binns2 and


M. Barbara E. Livingstone1
1
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Cromore Road, Coleraine, County Londonderry
BT52 1SA, UK
2
Nino Binns Consulting, Grange Rath, Drogheda, County Louth, Republic of Ireland

Abstract
The primary purpose of the present review was to determine if the scientific evidence available for potential human health benefits of
conjugated linoleic acid (CLA) is sufficient to support health claims on foods based on milk naturally enriched with cis-9, trans-11-CLA
(c9,t11-CLA). A search of the scientific literature was conducted and showed that almost all the promising research results that have
Nutrition Research Reviews

emerged in relation to cancer, heart health, obesity, diabetes and bone health have been in animal models or in vitro. Most human inter-
vention studies have utilised synthetic CLA supplements, usually a 50:50 blend of c9,t11-CLA and trans-10, cis-12-CLA (t10,c12-CLA). Of
these studies, the only evidence that is broadly consistent is an effect on body fat and weight reduction. A previous review of the relevant
studies found that 3.2 g CLA/d resulted in a modest body fat loss in human subjects of about 0.09 kg/week, but this effect was attributed to
the t10,c12-CLA isomer. There is no evidence of a consistent benefit of c9,t11-CLA on any health conditions; and in fact both synthetic
isomers, particularly t10,c12-CLA, have been suspected of having pro-diabetic effects in individuals who are already at risk of developing
diabetes. Four published intervention studies using naturally enriched CLA products were identified; however, the results were inconclu-
sive. This may be partly due to the differences in the concentration of CLA administered in animal and human studies. In conclusion,
further substantiation of the scientific evidence relating to CLA and human health benefits are required before health claims can be
confirmed.

Key words: Conjugated linoleic acid: Cis-9, trans-11-conjugated linoleic acid: Milk

Introduction acid containing conjugated double bonds. It is a group of


naturally occurring fatty acids synthesised as intermediates
The primary purpose of the present review was to deter-
mine if the level of scientific evidence available for poten- in the biohydrogenation of linoleic and linolenic acid in the
tial human health benefits of conjugated linoleic acid (CLA) rumen of animals, and thus is predominantly found in
is sufficient to support health claims on foods based on dairy products and ruminant meat(2). It can also be syn-
naturally CLA-enriched milk. Health claims on foods in thesised by industrial partial hydrogenation or alkali-iso-
Europe must now be selected from community lists of merisation of linoleic acid(3). CLA includes twenty-eight
approved claims or be the subject of a scientific dossier possible isomers, with two of these – cis-9, trans-11-CLA
to gain approval(1). In order to gain approval, the scientific (c9,t11-CLA) and trans-10, cis-12-CLA (t10,c12-CLA) –
evidence must be based on human studies, with human being known to possess biological activity(4). Commer-
intervention studies accorded a higher weighting(1). cially available CLA supplements usually contain c9,t11-
Cows’ milk contains predominantly the cis-9, trans-11 CLA and t10,c12-CLA at a ratio of approximately 1:1. The
isomer of CLA (c9,t11-CLA). Naturally CLA-enriched milk majority of CLA in the human diet occurs as c9,t11-CLA,
is defined for the purpose of the present review as milk with this isomer accounting for 85 –90% of the total CLA
obtained from grass-feeding regimens that have proven content in dairy products(5).
to result in higher levels of c9,t11-CLA than do convention- CLA was first discovered in 1932, by scientists at the Uni-
al feeding regimens (see below). versity of Reading (UK) who were investigating seasonal
‘Conjugated linoleic acid‘ is a term used to describe a variation in the vitamin content of milk(6). Interest in the
mixture of positional and geometric isomers of linoleic potential health benefits of CLA was later sparked by the

Abbreviations: BFM, body fat mass; CLA, conjugated linoleic acid; CRP, C-reactive protein; c9,t11-CLA, cis-9, trans-11-conjugated linoleic acid; LBM, lean
body mass; t10,c12-CLA, trans-10, cis-12-conjugated linoleic acid; UHT, ultra-high temperature.

* Corresponding author: Dr Tracy McCrorie, fax þ44 28 7032 3023, email t.mccrorie@ulster.ac.uk
Conjugated linoleic acid and health benefits 207

identification of CLA’s anti-carcinogenic activity in vitro, in Methods


extracts from fried ground beef(7). Since then, numerous
The overall purpose of the present review was to examine
studies and reviews have investigated the potential health
the current literature in relation to c9,t11-CLA and human
benefits of CLA, with purported health benefits including
health benefits with the focus on, in particular, milk and
anti-cancer, anti-atherogenic, anti-adipogenic, anti-diabeto-
dairy products where CLA content has been enhanced by
genic, anti-inflammatory and effects on bone health, at
natural feeding regimens. As there are relatively few
least in vitro.
studies on enhanced dairy products and in order to identify
CLA is present in relatively low quantities (mg) in meat
potential opportunities for future research on c9,t11-CLA,
and dairy products(2). Estimated dietary intakes from 3 d
studies on synthetic CLA isomers were also considered
diet records in the USA are 176 mg total CLA per d for
but not subject to exhaustive review. Much of the interest
men, with slightly lower intakes for women (104 mg/d).
in CLA has been provoked by promising results from
However, in the UK, intake of c9,t11-CLA was estimated
animal and in vitro studies and in order to put this in con-
to be 97.5 mg/d(8). Furthermore, this may vary depending
text, an overview of these studies is provided although this
on the method used to assess dietary intake(9). In recent
does not represent a complete picture of the large body of
times, there has been a surge of interest in increasing the
literature.
concentration of CLA in food in order to increase dietary
Initially, reviews were identified from PubMed and used
CLA intake. Cows’ milk fat is the richest natural source of
to provide an overview of the key areas of interest. Sub-
CLA(10); therefore, interest has focused on the potential
sequently, Medline, Embase and evidence-based medicine
Nutrition Research Reviews

for naturally increasing the c9,t11-CLA content of milk


(EBM) reviews (including Cochrane) were searched
and dairy products. Levels of CLA in milk fat ranging
via OvidSP (Wolters Kluwer, Alphen aan den Rijn, The
from 2 to 37 mg/g fat have been recorded and are due to
Netherlands) using the terms ‘CLA’, ‘conjugated linoleic
numerous factors(11). The composition of the animals’
acid’ and ‘dairy’, both separately and together. Thus, for
diet is a major factor, with cows that graze on fresh pasture
all databases, this yielded:
having higher concentrations of CLA in their milk fat than
those grazing on hay or concentrates(12). However, cows (a) 535 for ‘CLA’ (subheading: ‘conjugated linoleic acid’);
that are fed the same diet can demonstrate large intra- (b) 41 760 for ‘dairy’ (subheadings: ‘dairy products’ and
individual variation in CLA levels, which may be due to ‘milk’);
differences in metabolism and the rumen microflora (c) Combining both searches above yielded fifty-six
responsible for biohydrogenation(10). Altitude, breed and papers;
lactation age can also influence CLA levels(10). Research (d) Separate searches with the above databases for ‘cis-9,
in the UK has shown that there is no difference between trans-11’ yielded 13 525 papers;
the content of CLA in milk from organic and conventional (e) Medline was searched for ‘cis-9, trans-11’; only 4476
farms(13). Furthermore, it appears that processing of dairy papers were found and the introduction of ‘human’
products causes insignificant changes in CLA levels, par- reduced the number of papers to 1378. Further
ticularly compared with the large variations in CLA levels specification to linoleic acids, conjugated yielded 348;
due to diet and intra-individual variation(10). (f) Embase (n 9002) – narrowed to ‘humans’ and ‘CLA’
Much research has been carried out on strategies to (n 120);
manipulate the diets of cows to produce CLA-rich milk, (g) EBM reviews (n 37) – narrowed to ‘humans’ and
which can then be used to make CLA-rich dairy products. ‘CLA’ (n 35).
Supplementing the diets of cows with plant oils rich in
The searches were merged using a reference manager
linoleic or linolenic acid (such as sunflower-seed, soya-
programme and duplicates removed, with a total of 538,
bean or linseed oil) is known to cause an increase in the
the abstracts were then examined to determine whether
concentration of c9,t11-CLA in milk fat(14). A study which
the studies were relevant to the present review. A total of
evaluated the characteristics of naturally CLA-enriched
sixty-six human studies utilising observational, randomised
ultra-high temperature (UHT) milk, butter and cheese
control trials and crossover designs, published up to July
reported that although the sensory profiles of the CLA-
2011, were included in the present review. References
enriched products were different from those of control
within studies were also checked for completeness.
products, subjects did not rate the overall impression and
Reviews on animal studies were identified to provide
flavour as being different(15). It has also been shown that
an overview and then key references followed up
consumption of naturally CLA-enriched dairy products for
individually.
6 weeks, at similar levels to which conventional dairy pro-
ducts are habitually consumed in the UK, increases c9,t11-
CLA concentration in plasma lipids(16). Together these data
Conjugated linoleic acid and cancer
show that it is feasible and acceptable to increase c9,t11-
CLA intake in the human diet by producing naturally Since the initial identification of CLA from grilled minced
CLA-enriched dairy products for consumption. beef and its anticarcinogenic effects on skin cancer
208 T. A. McCrorie et al.

tumours in mice(7), the intervening years have provided a effects of CLA as an anti-carcinogenic agent, though
cascade of studies and reviews examining the anticarcino- in vitro and animal studies do demonstrate potential benefits.
genic properties of CLA. The mechanisms relating to anti- The manifestation of cancer is not a practical end-point in
carcinogenic properties of CLA are largely unresolved; human studies, combined with the numerous genetic and
CLA may act by antioxidant mechanisms, pro-oxidant environmental risk factors for different cancers. Conse-
cytotoxicity, inhibition of nucleotide and protein synthesis, quently, the majority of studies relating to CLA and cancer
reduction of cell proliferative activity and inhibition of both in humans are observational studies, particularly on breast
DNA –adduct formation and carcinogen activation(17 – 19). cancer (Table 1). Dietary and serum CLA was shown to be
The studies examined in these reviews have identified significantly lower in postmenopausal cases of breast
potential beneficial effects of CLA on colorectal, breast cancer compared with controls, thus suggesting a protective
and prostate cancer, with the majority of evidence from effect of CLA(30). In a continuation of this study, breast adi-
animal and in vitro studies. pose concentrations of CLA were not significantly different
CLA has shown consistent anticarcinogenic effects against between cases and controls(31). Furthermore, there was no
several types of experimental cancer(20) including breast association between breast adipose tissue CLA concen-
cancer(21,22). A review by Kelley et al.(19) examined the litera- tration and prognostic factors of breast cancer or occurrence
ture in terms of the effects of studies where purified isomers of metastases during a 7.5-year follow-up period(32). In the
of CLA were administered. Results from in vitro studies Netherlands Cohort Study on Diet and Cancer, intake of
suggest that the effects of the two isomers of CLA vary milk and milk products and meat products, as major sources
Nutrition Research Reviews

according to the cancer model examined. In the majority of dietary CLA, showed no relationship with breast cancer
of studies, c9,t11-CLA did not inhibit tumour growth, incidence in postmenopausal patients(33). This could be
whereas t10,c12-CLA demonstrated inhibitory effects in attributed to the fact that there were no significant differ-
studies using mouse and human mammary tumour cell ences in total CLA intake between cancer cases and
controls(33). The null association between breast cancer
lines. The t10,c12-CLA isomer also inhibited cell growth in
risk and intake of CLA was also demonstrated in a large
colon and gastric cancer cell lines. However, c9,t11-CLA
epidemiological study in Sweden(34). In contrast, in the
was more potent than t10,c12-CLA in colon cell lines
same cohort, women who consumed four or more servings
where both isomers were examined, though the optimal
of high-fat dairy foods per d (including whole milk, full-fat
concentration level varied between studies (50 mmol/l and
cultured milk, cheese, cream, soured cream and butter)
200 mmol/l)(23,24). Subsequent work by Yasui et al.(25) also
had a lower risk of developing colorectal cancer(35). It has
confirmed the chemopreventive effect of c9,t11-CLA against
been suggested that a higher intake of c9,t11-CLA confers
pre-initiation (dose-dependent) as well as post-initiation
a reduced risk of a specific type of breast cancer tumour in
stages of colorectal carcinogenesis (doses # 1% of diet).
premenopausal women. However, further investigation is
Overall, in studies using animal models of cancer, the
warranted, as the sample size was small(36).
purified c9,t11-CLA isomer reduced tumorigenesis in six
Recently, one small cross-over study examined colon
studies and showed no effect in two others(19). Similarly,
cancer markers after subjects (n 15) consumed milk natu-
the t10,c12-CLA isomer decreased tumorigenesis in six rally enriched with c9,t11-CLA or synthetically enriched
studies, but in contrast increased tumorigenesis in two with t10,c12-CLA or normal milk as a control(37). There
studies. Interestingly, three studies included in the present were large variations in the responses to supplementation
review found similar effects on the reduction of mammary across all three groups (NS), therefore all data were
tumours when a naturally enriched butter(26) and synthetic combined and a significant decrease in enzyme activity
isomers of c9,t11-CLA were fed to rats(27) and mice(28). b-glucosidase, nitroreductase and urease; P,0·01 between
Though more recent work suggests that t10,c12-CLA stimu- day 0 and day 56 was observed. The authors stated that this
lates mammary tumours in a mouse model, where the gene was important due to links between enzymic activity and
erbB2/her2 is over-expressed, application of c9,t11-CLA the production of carcinogens. However, it is important
showed no apparent effects(29). The same paper also to note that the main aim of the study was to examine
demonstrated that the reduction in tumours was in the the effects of CLA-enriched milk on lipid metabolism and
same order of magnitude irrespective of whether the CLA body composition(38).
source was natural or synthetic. The authors of this paper Currently the evidence for the anti-carcinogenic proper-
suggest that it would be prudent to avoid supplements ties of CLA in human subjects is limited to observational
containing t10,c12-CLA in those at risk of developing studies, with broader epidemiological evidence not speci-
breast cancer in which the erbB2/her2 gene is over- fically focusing on CLA but rather on milk and dairy
expressed (observed in 20–30% of human breast cancers), products. The World Cancer Research Fund & Association
whereas supplements containing c9,t11-CLA may be safe for International Cancer Research report reviewed the
and efficacious in breast cancer prevention(29). However, available evidence on the consumption of milk and links
due to the differences in proliferation of tumours by the with cancer(39). The report concluded that milk probably
site of cancer, combining results may not elicit the true protects against colorectal cancer, whereas there is limited
Conjugated linoleic acid and health benefits 209

Table 1. Effect of conjugated linoleic acid (CLA) on cancer in human subjects

Outcomes
Reference examined Number of subjects Design Overall result

Aro et al. Cancer (breast) 195 Cases; Case – control study. Postmenopausal women who consumed
(2000)(30) 208 controls, F Dietary intake of the lowest levels of CLA had a
CLA from FFQ 3.3-fold greater risk of breast cancer
than women who consumed the highest levels
Chajes et al. Cancer (breast) Cases 241 F; Case – control study. No association between CLA in breast
(2002)(31) controls 88 F CLA content of breast adipose tissue and breast cancer risk
adipose tissue
Voorrips et al. Cancer (breast) 941 Cancer cases, Prospective study, No evidence of a protective effect of higher
(2002)(33) 1598 cancer-free 6.4-year follow-up. CLA intake on breast cancer incidence
subjects Dietary CLA from FFQ in postmenopausal women
Chajes et al. Cancer (breast) 209 F Prospective study, No association between CLA in breast adipose
(2003)(32) 7.5-year follow-up. tissue and breast cancer risk or death
CLA content of breast
adipose tissue
McCann et al. Cancer (breast) Cases 1122 F; Case – control study. Very little association between CLA intakes
(2004)(36) controls 2036 F Dietary intake of CLA and breast cancer. However, relationship
and c9,t11-CLA from FFQ between c9,t11 intake and premenopausal.
women – reduced risk of ER-negative tumours
Larsson et al. Cancer (colon) 60 708 F Prospective study, Highest intake of CLA (. 149 mg/d) 29% less
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(2005)(35) 14.8-year follow-up. likely to develop colorectal cancer compared


Dietary intake with women with low intakes (, 73.4 mg/d)
of CLA from FFQ
Farnworth et al. Cancer (colon) 15 M þ F RCT, 8 weeks, cross-over. Inconclusive evidence but reductions in faecal
(2007)(37) Daily, 1 litre of control enzyme activity evident, but not attributable
milk (5 mg/g); naturally to changes in the population of one or
enriched milk more faecal bacteria – long-term effects
(32 mg c9,t11-CLA/d); of reducing these enzymes may be desirable
synthetically enriched
(t10,c12-CLA and
c9,t11-CLA 32 mg/g fat)
Larsson et al. Cancer (breast) 61 M, 433 F Prospective study, No evidence of protective effect of CLA on
(2009)(34) 17.4-year follow-up; breast cancer development
dietary intake from FFQ

F, female; c9,t11, cis-9, trans-11; ER, oestrogen receptor; M, male; RCT, randomised controlled trial; t10,c12, trans-10, cis-12.

evidence suggesting that cheese is a cause of colorectal overweight and obesity, let alone attenuate it, have
cancer. There is also limited evidence suggesting that con- remained largely elusive. More recently, obesity has been
sumption of milk conveys a protective effect against blad- recognised as a state of chronic or low-grade systemic
der cancer. In contrast, diets high in Ca are a probable inflammation, due to the abnormal circulating levels of
cause of prostate cancer, but there is limited evidence inflammatory molecules, including TNFa, leptin and IL-6,
suggesting that high consumption of milk and dairy pro- which are secreted by adipose tissue(41).
ducts is a cause of prostate cancer(39). Currently the evi- Studies in animals have shown that feeding CLA at levels
dence available is confusing, with suggestions that the of 0.5–1% of the diet reduces body fat in mice, chickens,
effects are dependent on the site of the cancer due to the hamsters, rats and pigs(42). The most substantial decreases
complex nature of diet, environment and nutrient inter- in body fat have been observed in mice, where CLA at
actions. However, a substantial amount of further work is levels of 0.5% of the diet has been shown to lower body
required to fully elucidate the potential anti-carcinogenic fat by 40 to 80%(42). This effect is thought to be attributable
properties of CLA in humans. to the t10,c12-CLA isomer, as the greatest body fat
reductions in mice were observed with a CLA mix with a
higher proportion of t10,c12-CLA than c9,t11-CLA(43).
Conjugated linoleic acid and body composition Also, in vitro, t10,c12-CLA prohibits TAG accumulation in
The overwhelming increases in the proportion of over- cultures of differentiating human preadipocytes, whereas
weight and obesity in the world have been the focus of c9,t11-CLA increases TAG content(43). Evidence suggests
much debate and research. Currently two-thirds of the that this effect may be due in part to a reduction in lipid
UK adult population are classified as overweight or uptake by adipocytes due to effects of CLA on stearoyl-
obese (BMI . 25 kg/m2)(40). Obesity is a multifaceted dis- CoA desaturase and lipoprotein lipase activity(4).
order, largely driven by its co-morbidities including type 2 Promising evidence from animal studies led to an array
diabetes, insulin resistance and CVD. To date feasible and of human intervention studies being carried out investi-
sustainable approaches to prevent further increases in gating the effect of CLA on body composition in normal
210 T. A. McCrorie et al.

weight, overweight and obese subjects. The majority of significant BFM reductions in normal-weight adults,
these studies used a 50:50 (c9,t11-CLA and t10,c12-CLA) subjects were involved in physical training throughout
CLA mix, and results have been inconsistent. Almost all the supplementation periods, which may potentially be a
of these studies have shown no effect on body weight; confounder(53 – 55).
however, some have reported reduced body fat mass In overweight and obese human subjects (Table 3),
(BFM) following supplementation with CLA, as discussed 50:50 CLA given at doses of 1.7–6.8 g/d, over periods of
in detail below. 4 to 104 weeks, has resulted in non-significant BFM
The body composition studies conducted in normal- changes in some instances(57 – 63), and reductions of
weight adults (Table 2) have supplemented with 3– 15% in other studies(50,57 – 63,77,78). The greatest reduction
0.7–5.5 g 50:50 CLA/d, for 4–16 weeks, and of those in BFM (14.8%) was observed in a study of patients
which measured BFM, some have reported non-significant on blood pressure-lowering medication, who were sup-
changes(44,46,47,50,79,175), and others have reported BFM plemented with 4.5 g 50:50 CLA/d for 8 weeks(71).
reductions of 4% up to 20%(51 – 56). However, it is important In apparently healthy adults, the greatest reduction in
to note that in some of the studies that have reported BFM (6%) was observed in the study by Gaullier et al.(66)

Table 2. Effect of conjugated linoleic acid (CLA) on body composition in normal-weight human subjects

Reference Form of CLA Number of subjects Design Overall result


Nutrition Research Reviews

Thom et al. CLA mixture 10 M, 10 F RCT, 12 weeks, No significant change in


(2001)(53)* 1.8 g CLA/d body weight. Significant decrease
in BFM (20%)
Mougios & CLA mixture 13 M, 9 F 8 weeks, 0.7 g No significant change in body weight.
Vessby (2001)(51) CLA/d for weeks 1 – 4, Significant decrease in
1.4 g CLA/d for BFM (skinfolds) with 1.4 g CLA
weeks 5 – 8
Smedman et al. CLA mixture 80 M þ F RCT, 12 weeks, No significant change in body weight.
(2001)(52) 4.2 g CLA/d Significant decrease in BFM (4%)
Noone et al. CLA mixture or 80:20 c9,t11 18 M, 33 F 8 weeks, 3 g 50:50 CLA/d No significant change in body weight.
(2002)(106) and t10,c12-CLA or 3 g 80:20 CLA/d BFM not determined
Kreider et al. CLA mixture (Tonalin) 23 M RCT, with resistance No significant change in body weight
(2002)(175) training, 28 d, or BFM
6 g CLA mixture/d
Belury et al. CLA mixture 21 M þ F 8 weeks, 6 g CLA/d No significant change in body weight.
(2003)(74) BFM not determined
Petridou et al. CLA mixture 16 F RCT, 6 weeks, 2.1 g CLA/d No significant change in body weight
(2003)(44) or BFM
Tricon et al. c9,t11- or t10,c12-CLA 39 – 49 M RCT, cross-over, 8 weeks, No significant change in body weight
(2004)(79) 0.59, 1.19 or 2.38 g or BFM
c9,t11-CLA/d or 0.6,
1.3 or 2.5 g t10,c12-CLA/d
Tricon et al. Supplemented cows’ 32 M RCT, cross-over, 6 weeks, No significant change in body weight.
(2006)(45) diets to produce milk 0.15 or 1.42 g c9,t11-CLA/d BFM not determined
naturally enriched
with c9,t11-CLA to
make products
Colakoglu et al. CLA mixture 44 F RCT, 6 weeks, 3.6 g CLA/d No significant change in body weight.
(2006)(54)* Significant decrease in BFM (8%)
Pinkoski et al. CLA mixture 42 M, 43 F RCT, 7 weeks, 5 g CLA/d No significant change in body weight.
(2006)(55)* Significant decrease in BFM (4%)
Lambert et al. CLA mixture 62 M þ F RCT, 12 weeks, 3.9 g CLA/d No significant change in body weight
(2007)(46) or BFM
Nazare et al. CLA mixture, 44 M þ F RCT, 14 weeks, 3.8 g CLA/d No significant change in body
(2007)(47) added to yoghurt weight or BFM
Raff et al. CLA mixture 75 F RCT, 16 weeks, 5.5 g CLA/d or Significant decrease in BFM (4%)
(2009)(56) or c9,t11-CLA 5.5 g c9,t11-CLA/d and lower-body fat mass (7%)
with CLA mixture
Wanders et al. Foods enriched with 25 M, 36 F RCT, crossover, 21 d, oleic No significant changes in body weight
(2010)(49) CLA-rich oil, 7% of (control) or industrial between diets
total energy as CLA trans-fatty acids or 26.8 g
(78% c9,t11-CLA and CLA isomers/d
17% t10,c12-CLA)
Brown et al. Beef and dairy products 18 F RCT, 56 d, 1.17 g CLA/d No significant changes in body weight,
(2011)(50) rich in CLA from BFM or LBM
pasture-fed dairy cattle

CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; M, male; F, female; RCT, randomised controlled trial; BFM, body fat mass; c9,t11, cis-9, trans-11; t10,c12,
trans-10, cis-12; LBM, lean body mass.
* Subjects exercising.
Nutrition Research Reviews
Table 3. Effect of conjugated linoleic acid (CLA) on body weight or body composition in overweight and obese human subjects

Reference Form of CLA Number of subjects Design Overall result


(59)
Berven et al. (2000) CLA mixture 17 F, 30 M RCT, 12 weeks, 3.44 g CLA/d No significant change in body weight or BFM
Blankson et al. (2000)(64) CLA mixture 47 M þ F RCT, 12 weeks, 1.7, 3.4, 5.1 No significant changes in body composition
or 6.8 g CLA/d between groups. Significant reduction in BFM
within 3.4 and 6.8 g/d groups (6%), no additional
effect with 6.8 g/d over that seen with 3.4 g/d
Risérus et al. (2001)(101) CLA mixture 24 M RCT, 4 weeks, 4.2 g CLA/d No significant change in weight. BFM not
determined. Significant decrease in SAD
(measure of abdominal obesity)
Risérus et al. (2002)(60) CLA mixture or t10,c12-CLA 57 M RCT, 12 weeks, 3.4 g CLA No significant difference in body composition
or t10,c12-CLA/d between the groups. Significant decrease
in weight, SAD and BFM within t10,c
12-CLA group. Significant decrease in SAD
and BFM within CLA group
Risérus et al. (2004)(78) c9,t11-CLA 25 M RCT, 12 weeks, 3 g c9,t11-CLA/d No significant change in body weight between
c9,t11-CLA and placebo. Significant increase

Conjugated linoleic acid and health benefits


in body weight within c9,t11-CLA group
Gaullier et al. (2004)(65) CLA mixture 31 M, 149 F RCT, 1 year, 3.6 g CLA-NEFA/d Significant reduction in body weight (1%) and
or 3.4 g CLA-TAG/d BFM (5%). No effect on LBM
Malpuech-Brugère et al. (2004)(77) c9,t11- or t10,c12-CLA 82 M þ F RCT, 18 weeks, 1.5 or 3 g c9,t11-CLA No significant changes in body composition
or 1.5 or 3 g t10,c12-CLA per d
Desroches et al. (2005)(80) Supplemented cows’ 16 M RCT, cross-over, 4 weeks, 0.24 or No significant change in body weight. BFM
diets to produce 2.5 g c9,t11-CLA/d not determined
butter naturally enriched
with c9,t11-CLA
Gaullier et al. (2005)(66) CLA mixture 24 M, 110 F Continuation of 2004 study(65), 2 years, Significant decrease in body weight (2%)
3.4 g CLA-TAG/d and BFM (6%), no safety issues with long-term
supplementation
Naumann et al. (2006)(102) c9,t11- or t10,c12-CLA 48 M, 39 F RCT, 13 weeks, 3 g c9,t11-CLA No significant change in body weight.
in a dairy drink or t10,c12-CLA per d BFM not determined
(67)
Gaullier et al. (2007) CLA mixture (Clarinol) 93 M þ F RCT, 6 months, 3.4 g CLA/d BFM was significantly decreased at 3 months
(1%) and 6 months (3.4%). Most BFM reduction
was in legs, LBM increased
Laso et al. (2007)(68) CLA mixture (Tonalin) added 33 M, 11 F RCT, 12 weeks, 3 g CLA/d Significant decrease in BFM (3%) in overweight
to skimmed milk subjects, but not in obese subjects
Watras et al. (2007)(69) CLA mixture 8 M, 32 F RCT, 6 months, 3.2 g CLA/d Significant decrease in BFM (4%) and
body weight (1%)
Steck et al. (2007)(57) CLA mixture 13 M, 35 F RCT, 12 weeks, 3.2 or 6.4 g CLA/d No significant change in body weight or BFM.
Significant increase in LBM within 6.4 g/d group
(58)
Syvertsen et al. (2007) CLA mixture (Clarinol) 18 M, 65 F RCT, 6 months, 3.4 g CLA/d No significant change in body weight or BFM.
Significant decrease in waist circumference
in CLA group
Norris et al. (2009)(70) CLA mixture 35 F RCT, cross-over, 16 weeks, 6.4 g CLA/d Significant reduction in BMI and BFM,
no effect on LBM
Herrmann et al. (2009)(61) c9,t11-CLA or t10,c12-CLA 34 M RCT, crossover, 4 weeks, 3.4 g CLA/d No significant change in body weight, BMI, waist
or CLA mixture circumference or waist:hip ratio
(71)
Zhao et al. (2009) CLA mixture 44 M, 36 F (subjects RCT, 8 weeks, 4.5 g CLA/d Significantly lower %BFM and hip circumference.
taking blood No significant change in body weight, BMI,
pressure medication) waist circumference or waist:hip ratio
Racine et al. (2010)(73) CLA mixture in chocolate milk 53 children 6 – 10 years RCT, 7 months, 3 g CLA/d CLA group had significantly less abdominal
body fat (%)
(62)
Sluijs et al. (2010) c9,t11-CLA manufactured from 167 M, 179 F RCT, 6 months, 4 g CLA/d No significant change in body weight, BMI,

211
safflower-seed oil waist circumference or waist:hip ratio
212 T. A. McCrorie et al.

which was of 104 weeks’ duration, and supplemented with

No significant changes in body weight, BFM or LBM

CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; F, female; M, male; RCT, randomised controlled trial; BFM, body fat mass; SAD, sagittal abdominal diameter; t10,c12, trans-10, cis-12; c9,t11, cis-9, trans-11; LBM, lean
CLA group had significantly lower weight and BMI
3.4 g 50:50 CLA/d. One study in children found that body
fat gain was attenuated during prepubertal growth in

No significant change in body weight, BFM,


6– 10-year-olds supplemented with 3.0 g 50:50 CLA/d(73).
However, in a few cases it has been noted that the largest
reduction in BFM occurs in the lower body (for example,
legs)(56,67). Furthermore, some studies have reported
increases in lean body mass (LBM) with CLA supplemen-
tation(57,64,67). In the study by Blankson et al.(64) increased
LBM was only observed in the group which significantly
BMI or LBM increased their level of intensive physical training during
Overall result

the intervention, hence it is possible that the observed


effects were, at least partially, due to increased physical
activity and not CLA supplementation.
Interestingly, in another study, overweight subjects
receiving 3.2 g of 50:50 CLA per d over a 6-month period,
including the Christmas period, demonstrated a lower rate
of weight gain and a 4% reduction in BFM compared with
Nutrition Research Reviews

control(69). A study of subjects with type 2 diabetes sup-


RCT, 12 weeks, 4.5 g CLA/d

plemented with 6 g of 50:50 CLA per d for 8 weeks found


RCT, crossover, 8 weeks,
RCT, 56 d, 1.17 g CLA/d

that plasma concentration of t10,c12-CLA, but not c9,t11-


CLA, was inversely associated with body weight, suggesting
that t10,c12-CLA is the active CLA isomer in relation to
3.5 g CLA/d

weight change(74). This is in agreement with evidence from


or placebo

animal studies which also points to the t10,c12-CLA isomer


Design

as being the CLA isomer which elicits BFM reductions.


A meta-analysis concluded that CLA, at a dose of 3.2 g/d,
produces a modest body fat loss in humans of about
0.09 kg/week, with the relationship being linear up to 6
Number of subjects

months(75). This may be partly explained by the isomer-


and tissue-specific effects of CLA, whereby c9,t11-CLA was
found to be increased in skeletal muscle and t10,c12-CLA
13 M, 13 F

was incorporated into adipose tissue TAG in a subset of


27 M

healthy non-obese participants(76).


18 F

In addition to studies examining effects of CLA mixes,


a number of studies have investigated the effects of
Beef and dairy products rich in CLA

individual CLA isomers on body composition. Findings


from pasture-fed dairy cattle

from these studies show that consumption of 0.59–3 g


c9,t11-CLA or CLA mixture

c9,t11-CLA per d or 0.6–3.4 g t10,c12-CLA per d does not


change body composition(60,77 – 79).
CLA mixture (Tonalin)

added to yoghurt

Currently, only three studies have been carried out


which have fed subjects naturally CLA-enriched dairy
Form of CLA

products and investigated the effects on body compo-


sition(45,50,80). In the study by Desroches et al.(80), sixteen
normolipidaemic overweight and obese men consumed
butter naturally enriched with CLA (c9,t11-CLA; 2.59 g/d),
or non-enriched control butter (0.24 g/d), for 4 weeks
each in a cross-over design, and results showed no
MacRedmond et al. (2010)(72)

changes in body composition. Tricon et al.(45) fed


thirty-two healthy normolipidaemic men either naturally
Joseph et al. (2011)(63)
Brown et al. (2011)(50)

CLA-enriched or control dairy products (UHT full-fat


Table 3. Continued

milk, butter and cheese (1.42 v. 0.15 g c9,t11-CLA/d) in a


6-week cross-over study. Similarly, no changes in body
body mass.
Reference

weight were observed; however, body composition was


not the primary outcome of this study, but rather blood
lipid profile. No changes in body composition were
Conjugated linoleic acid and health benefits 213

observed when subjects consumed beef and dairy products evidence of opposing effects of CLA isomers, with one
naturally enriched with 1.17 g CLA/d for 56 d(50). Also, with study in mice showing c9,t11-CLA decreasing and
all of these studies it is important to note that the durations t10,c12-CLA increasing atherosclerotic lesion area(93).
(4 –8 weeks) were relatively short for investigating effects Further to the above studies which have supplemented
on body composition. animals’ diets with commercial CLA preparations, studies
There are many possible explanations for the lack of have been carried out to investigate the anti-atherogenic
reproducibility in studies of CLA’s effect on body compo- effects of inclusion of dairy foods, and other foods such
sition between animals and humans. These include age, as eggs, naturally enriched with CLA, into the diets of ani-
sex, genetic predisposition to fat accumulation and differ- mals(94 – 98). The results of these studies have shown that
ences in experimental design(81). It is interesting to note CLA can improve plasma lipid profile and decrease athero-
that although animal studies have evaluated the effects of sclerosis-related biomarkers. Overall, at present there is no
CLA on weight gain over time in growing animals, the general consensus as to the effect of CLA supplementation
majority of human studies tend to investigate whether on lipids or atherosclerosis in animals. Furthermore, most
CLA affects weight or fat loss only in adults. animal studies that have suggested protective anti-athero-
genic effects have generally provided CLA doses greater
than those achievable in the human diet.
Conjugated linoleic acid, lipid metabolism and
Despite much investigation, the precise mechanisms by
atherosclerosis
which CLA affects lipid metabolism and adipose tissue are
Nutrition Research Reviews

CVD are the leading cause of mortality globally(82) and so not fully elucidated. However, it is thought that CLA modu-
modification of key risk factors such as LDL-cholesterol or lates energy expenditure, apoptosis, fatty acid oxidation,
blood TAG are key targets (for example, in the UK(83)). The lipolysis and lipogenesis(99). As discussed in the previous
impact of dietary fat and specific fatty acids on blood lipids section, the t10,c12-CLA isomer is thought to exert effects
has been a focus of research at least since Keys et al.’s early on body composition, partly due to a reduction in lipid
epidemiological work(84), so it is not surprising that the uptake by adipocytes due to effects of CLA on stearoyl-
effect of CLA on blood lipids has been investigated. CoA desaturase and lipoprotein lipase activity(4).
Evidence from animal studies in rabbits, hamsters and In humans epidemiological studies on dietary CLA
mice has suggested that CLA has the potential to modulate intakes and prevalence of atherosclerosis have not been
plasma lipid metabolism and make an impact on the devel- carried out to date. However, over the past decade,
opment and regression of cholesterol-induced athero- numerous human intervention studies have investigated
sclerotic plaques(85). the effect of CLA on lipids and other markers of
In rabbits, mixed-isomer CLA, fed at levels of 0.1– 1% of atherosclerotic risk (Table 4), the results of which have
diet over periods of 13 to 22 weeks, has been shown to been highly inconsistent, possibly due to the use of
reduce cholesterol deposition in the aorta(86) and result different isomers and varying doses. The majority of
in significant regression of established atherosclerotic these studies have used commercial mixed- or pure-
lesions(87). Furthermore, mixed-isomer CLA at a lower isomer CLA preparations, at levels of 1.7 to 6.8 g/d,
dose (0.05%) has been shown to be sufficient to decrease over periods of 4 to 13 weeks, and have not shown any
lesion development in rabbits(88). Supplementation with overall effect on plasma lipid or lipoprotein concentrations,
either c9,t11-CLA or t10,c12-CLA results in similar compared with placebo, in normal-weight and overweight
reductions in lesion development to that seen with subjects(44,46,50,52,61 – 64,73,78,100 – 105). However, one study
mixed-CLA isomer supplementation(89). did report significant within-group reductions in total
Studies in hamsters that have supplemented with CLA cholesterol and LDL-cholesterol with doses of 1.7 and
over periods of 6–12 weeks, using different CLA isomers 3.4 g CLA/d(64), but it was stated that the reductions were
and doses, have shown mixed results, but there is evidence not clinically important.
of improvements in lipid profile(90,91). In addition, there is Some studies have reported that supplementation
some indication that CLA in conjunction with a lower-fat with commercial CLA preparations can have a negative
diet may reduce atherosclerotic lesions in the hamster(85). effect on the lipid profile. For example, a significant
It has been suggested that t10,c12-CLA may be the protec- decrease in HDL-cholesterol was observed on supple-
tive isomer in relation to lipid profile, as in the study by menting with 3.4 g t10,c12-CLA per d in obese men with
Gavino et al.(91), a CLA mix, but not the c9,t11-CLA the metabolic syndrome(60), and in healthy subjects who
isomer, improved the lipid profile of hamsters. were supplementing their diets with 0.7–1.4 g CLA mix
In mice, studies with supplemental CLA carried out over per d(51). There is some evidence to suggest that CLA
periods of 4–20 weeks, using different CLA isomers and (mixtures and individual isomers) can induce lipid per-
doses, have also shown mixed results(85). There has been oxidation(78,103); however, it is not known whether this
one promising report of CLA (80:20 blend of c9,t11-CLA effect of CLA could be pro-atherogenic in humans.
and t10,c12-CLA) resulting in marked regression of athero- In contrast, other studies have shown a positive effect
sclerotic lesions in apoE mice(92). In addition, there is some of CLA, with 3 g 50:50 CLA mix per d lowering fasting
Nutrition Research Reviews

214
Table 4. Effect of conjugated linoleic acid (CLA) on blood lipid concentrations in human subjects

Reference Form of CLA Number of subjects Design Overall result

Blankson et al. CLA mixture 47 M þ F RCT, 12 weeks, 1.7, 3.4, 5.1 or 6.8 g CLA/d No significant effect on HDL, LDL or tChol
(2000)(64) between groups
Mougios et al. CLA mixture 13 M, 9 F 8 weeks, 0.7 g CLA/d for weeks 1 – 4, Significant decrease in HDL
(2001)(51) 1.4 g CLA/d for weeks 5 – 8
Risérus et al. CLA mixture 24 M RCT, 4 weeks, 4.2 g CLA/d No significant effect on cholesterol or TAG
(2001)(101)
Benito et al. CLA mixture 17 F RCT, 13 weeks, 3.9 g CLA/d No significant effect on HDL, LDL, tChol or TAG
(2001)(100)
Smedman & CLA mixture 50 M þ F RCT, 12 weeks, 4.2 g CLA/d No significant effect on apoA-1, apoB, HDL,
Vessby LDL, NEFA, tChol, TAG or VLDL
(2001)(52)
Noone et al. CLA mixture or 80:20 c9,t11 18 M, 33 F 8 weeks, 3 g 50:50 CLA or 3 g 80:20 CLA per d 50:50 CLA decreased TAG, 80:20 CLA
(2002)(106) and t10,c12-CLA decreased VLDL
Risérus et al. CLA mixture or t10,c12-CLA 57 M RCT, 12 weeks, 3.4 g CLA or t10,c12-CLA per d Significant decrease in HDL with both CLA
(2002)(60) mix and t10,c12-CLA
Petridou et al. CLA mixture 16 F RCT, 6 weeks, 2.1 g CLA/d No significant effect on tChol, TAG or HDL
(2003)(44)
Moloney et al. CLA mixture 32 M þ F RCT, 8 weeks, 3 g CLA/d Significant increase in HDL, and decrease in
(2004)(107) LDL:HDL
Tricon et al. c9,t11- or t10,c12-CLA 39 – 49 M RCT, cross-over, 8 weeks, 0.59, 1.19 or 2.38 g t10,c12-CLA increases LDL:HDL and total
(2004)(134)

T. A. McCrorie et al.
c9,t11-CLA/d or 0.6, 1.3 or 2.5 g t10,c12-CLA/d cholesterol:HDL, but c9,t11-CLA
decreases these
Risérus et al. c9,t11-CLA 25 M RCT, 12 weeks, 3 g c9,t11-CLA/d No significant effect on HDL, LDL, tChol, TAG
(2004)(78) or VLDL. Significant increase in lipid
peroxidation (8-iso-PGF2a and
15-keto-dihydro-PGF2a)
Naumann et al. c9,t11- or t10,c12-CLA 48 M, 39 F RCT, 13 weeks, 3 g c9,t11-CLA or t10,c12-CLA per d No significant effect on TAG, HDL or LDL
(2006)(102) in a dairy drink
Lambert et al. CLA mixture 62 M þ F RCT, 12 weeks, 3.9 g CLA/d No CLA specific effects. tChol and LDL
(2007)(46) significantly decreased in both groups
and HDL decreased in women
Raff et al. Foods baked with butter 38 M RCT, 5 weeks, 4.6 g CLA/d No significant effect on HDL, LDL, tChol
(2008)(103) synthetically enriched with or TAG. Significant increase in lipid
CLA mixture peroxidation (8-iso-PGF2a)
Turpeinen et al. c9,t11-CLA 12 M, 28 F RCT, 12 weeks, 2 g CLA/d No significant changes in plasma lipids
(2008)(104)
Herrmann et al. c9,t11-CLA or t10,c12-CLA 34 M RCT, crossover, 4 weeks, 3.4 g CLA/d No significant changes in tChol, HDL, LDL,
(2009)(61) or CLA mixture TAG or blood pressure
Zhao et al. CLA mixture 44 M, 36 F (subjects taking RCT, 8 weeks, 4.5 g CLA/d Significant effects on HDL, LDL:HDL, blood
(2009)(71) blood pressure medication) pressure. No significant effect on tChol, LDL,
TAG or VLDL
Racine et al. CLA mixture in chocolate milk 53 children aged 6 – 10 years RCT, 7 months, 3 g CLA/d No significant changes in LDL. CLA group had
(2010)(73) significant decreases in HDL
Sluijs et al. c9,t11-CLA manufactured from 167 M, 179 F RCT, 6 months, 4 g CLA/d or placebo No significant effect on HDL, LDL, TAG, tChol
(2010)(62) safflower-seed oil or blood pressure
Wanders et al. Foods enriched with CLA-rich oil, 25 M, 36 F RCT, crossover, 21 d, oleic (control) or industrial Significantly higher tChol, HDL, LDL, apoB
(2010)(49)* 7% of total energy as CLA trans-fatty acids or 26.8 g CLA isomers/d relative to control diet. No significant difference
(78% c9,t11-CLA and in TAG
17% t10,c12-CLA)
Conjugated linoleic acid and health benefits 215

TAG, and 3 g 80:20 CLA mix per d decreasing VLDL, in

No significant effect on tChol, TAG, HDL, LDL,


healthy subjects(106). Furthermore, 3 g 50:50 CLA per d

No significant changes in tChol, TAG, HDL,


was shown to significantly increase HDL-cholesterol and
significantly decrease LDL:HDL-cholesterol in patients

No significant effect on blood pressure


with type 2 diabetes(107). Consumption of foods enriched
with 26.8 g CLA/d led to a significant positive effect
on HDL concentration and a significant lowering of
LDL-cholesterol(49). Interestingly, Tricon et al.(79) observed

VLDL or oxidised LDL


divergent responses in plasma lipids with CLA supplemen-

LDL, VLDL or IDL


tation, with t10,c12-CLA (0.6 –2.5 g/d) increasing LDL:HDL-
cholesterol and total:HDL-cholesterol and c9,t11-CLA
Overall result

CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; M, male; F, female; RCT, randomised controlled trial; tChol, total cholesterol; c9,t11, cis-9, trans-11; t10,c12, trans-10, cis-12.
(0.59 –2.38 g/d) decreasing these ratios, with no dose-
dependent effect observed. Elevated cholesterol ratios of
LDL:HDL and total:HDL-cholesterol are independent risk
factors for CHD(108,109).
Recently, the effects of consuming dairy products,
naturally rich in CLA or naturally enriched with CLA,
RCT, crossover, 21 d, oleic (control) or industrial

on lipids in human subjects have been examined in four


trans-fatty acids or 26.8 g CLA isomers/d
Nutrition Research Reviews

studies(45,50,80,110). Three of these studies manipulated


RCT, crossover, 8 weeks, 3.5 g CLA/d

cows’ diets to produce dairy products naturally enriched


with CLA(44,50,80). In the study by Desroches et al.(80),
normolipidaemic overweight and obese men consumed
butter naturally enriched with CLA (c9,t11-CLA; 2.59 g/d),
RCT, 56 d, 1.17 g CLA/d

or non-enriched control butter (0.24 g/d), for 4 weeks.


Results showed plasma lipid subfraction levels (VLDL,
LDL and HDL) were not significantly different between
the two treatments; however, consumption of the non-
enriched butter resulted in a significantly greater reduction
Design

of total cholesterol, total:HDL-cholesterol and LDL:


HDL-cholesterol compared with the CLA-enriched butter,
a result which was contradictory to the hypothesis.
Tricon et al.(45) fed healthy normolipidaemic men either
naturally CLA-enriched or control dairy products (UHT
full-fat milk, butter and cheese (1.42 v. 0.15 g c9,t11-CLA
Number of subjects

per d)) in a 6-week cross-over study. Overall, lipid


subfractions were not affected; however, a small but signi-
25 M, 36 F

ficant increase in LDL:HDL-cholesterol was observed.


These results were similar to findings by Brown et al.(50)
27 M
18 F

where consumption of beef and dairy products rich in


CLA (1.17 g CLA/d) for 56 d did not alter blood lipid profile.
A small, cross-over study in ten healthy subjects found
Beef and dairy products rich in CLA
energy as CLA (78% c9,t11-CLA

that consumption of cheese made from naturally CLA-rich


from pasture-fed dairy cattle

sheep’s milk (0.25 g c9,t11-CLA per d) for 10 weeks had


c9,t11-CLA or CLA mixture
CLA-rich oil, 7% of total

and 17% t10,c12-CLA)

no effect on plasma lipids, as compared with consumption


* Same study with results reported over two papers.

of a regular cows’ cheese(110). The daily intake of CLA was


Foods enriched with

added to yoghurt

confirmed as being 0.25 g c9,t11-CLA in correspondence


with the author. It is important to note that using cows’
Form of CLA

milk cheese as a control was not ideal, due to the fact


that it has a very different fatty acid profile compared
with sheep’s cheese. Overall these studies have shown
no significant effect of treatment with dairy products
Table 4. Continued

naturally rich in CLA or naturally enriched with CLA on


Engberink et al.
(2011)(105)*

Joseph et al.

plasma lipids.
Brown et al.
(2011)(50)

(2011)(63)
Reference

Dairy products which are naturally enriched in CLA are


also higher in trans-vaccenic acid (trans-18 : 1), lower in
SFA content, and slightly higher in n-3 PUFA content
216 T. A. McCrorie et al.

than conventional dairy products, due to the feeding strat- other markers of inflammation did not change(127). Butz
egies employed for enrichment(15). It has been suggested et al.(126) reported that mice fed 0.5% CLA mix for
that consuming trans-fatty acids impairs the lipid profile 3 weeks had less plasma TNFa compared with mice
by lowering HDL-cholesterol and raising LDL-cholesterol on a control diet. In pigs fed 2% CLA mix for 14 d,
levels(111). Whether the content of trans-vaccenic acid in a decrease in induced elevation and mRNA expression
naturally CLA-enriched dairy products could counteract of pro-inflammatory cytokines (IL-6 and TNF-a), and
the potential benefit of CLA on the lipid profile unclear. an increase in an anti-inflammatory cytokine (IL-10) were
The current evidence examining the intake of trans-fatty observed. Furthermore, a molecular aspect of the same
acids from animal sources and associations with CHD study determined t10,c12-CLA to be the main isomer to
presents a confusing picture, particularly given the higher which the anti-inflammatory effect can be attributed(125).
than typically consumed levels of trans-fatty acids used However, in contrast to these findings, two studies have
within studies(112 – 116). However, it is unclear whether the established t10,c12-CLA to have pro-inflammatory effects,
partial conversion of trans-vaccenic to c9,t11-CLA in where mice fed 0.5% t10,c12-CLA for 14 d showed induced
human intestines, liver and adipose tissue promotes pro-inflammatory cytokine transcripts in white adipose
adverse or beneficial effects on lipid profile(113,117). tissue(128), and short-term supplementation with t10,c12-
The reason for the inconsistent and mostly neutral CLA in mice also increased pro-inflammatory cytokine
results in relation to the effects of CLA on lipids in gene expression in a study(129).
human studies compared with animal studies is unclear. Human intervention studies have investigated the
Nutrition Research Reviews

However, it is important to note that while animal studies effect of CLA (both commercial preparations and naturally
examined the effect of using CLA to supplement hyper- CLA-enriched dairy products) on various biomarkers of
lipidaemic animals that were eating atherogenic diets, inflammation (Table 5). Results to date have been mixed,
human studies examined the effect of supplementing with most studies either showing an increase in inflam-
diets of normolipidaemic subjects with CLA. Furthermore, matory markers, or no change. Three studies that have
it is conceivable that the anti-atherosclerotic effects of supplemented subjects with a CLA mixture at doses of
CLA observed in animal studies may be due to mechanisms 4.2 to 6.4 g/d, over periods of 12 to 16 weeks, have
other than effects on lipids, for instance anti-inflammatory found increases in plasma levels of C-reactive protein
effects, as atherosclerosis is an inflammatory disease. (CRP)(57,130,131). There were no significant effects on
inflammatory markers including CRP and a range of inter-
leukins when subjects were supplemented with 4 to 4.5 g
Conjugated linoleic acid, inflammation and immune
CLA mixture/d(132,133). Two studies with CLA added to
effects
foods showed no effect on plasma CRP levels; however,
Inflammation underlies a wide range of conditions. For the duration of these trials was relatively short (5 and 8
example, as noted above, obesity is now recognised as weeks)(63,103). Furthermore, two crossover studies that
a state of chronic or low-grade systemic inflammation, provided c9,t11-CLA at doses of 4 g/d(62) or 0.6–2.4 g/d
due to the abnormal circulating levels of inflammatory mol- and 0.6–2.5 g/d t10,c12-CLA(134), for 6 months and 8
ecules, including TNFa, leptin and IL-6, which are secreted weeks respectively, observed no change in plasma CRP
by adipose tissue(41). In addition, inflammation is central concentrations.
to atherosclerosis(118) and the metabolic syndrome(119). Supplementation with t10,c12-CLA at doses of 3–3.4 g/d
In vitro studies have shown that CLA has anti-inflamma- for 12–13 weeks has produced inconsistent results.
tory effects. CLA (CLA mix, or c9,t11-CLA or t10,c12-CLA) is A study in obese men with the metabolic syndrome
associated with a lower mRNA expression of the inflamma- found increased plasma CRP levels; on the other hand,
tory mediators cyclo-oxygenase-2, TNFa, and inducible a study in overweight men and women demonstrated no
NO synthase, and decreases production of induced PGE2, effect on plasma CRP, or on other markers of inflam-
NO, IL-6 and IL-1b in mouse macrophage cells(120). The mation(135,136). In the case of c9,t11-CLA, supplementation
c9,t11-CLA isomer inhibits induced eosinophil activation, with similar doses (3 g) for similar durations (12 –13
decreases transcription of TNFa, IL-6 and IL-12 in Caco-2 weeks) has also resulted in contrasting results, with one
cells and enhances IL-10 production in murine dendritic study reporting increased excretion of a pro-inflammatory
cells(121 – 123). Furthermore, both c9,t11-CLA and t10,c12- marker (15-keto-dihydro-PGF2a) in obese subjects(78),
CLA reduce PGE2 and thromboxane B2 concentrations in and another study reporting no effect on a range of
human macrophages(124). pro-inflammatory markers in overweight subjects(135).
Animal studies have been carried out to determine if As described in the previous section, the effect of feed-
CLA exerts anti-inflammatory effects in vivo; however, ing subjects dairy products which are naturally enriched
results to date have been inconsistent. Three animal studies in c9,t11-CLA (due to the manipulation of diets of cows)
have found a CLA mix to be anti-inflammatory(125 – 127). has been investigated in two studies to date(45,80). In these
Obese rats fed 1.5% CLA mix for 8 weeks were found studies, daily doses of 1.4–2.6 g c9,t11-CLA were fed for
to have less adipose TNFa mRNA expression; however, durations of 4–6 weeks, and no changes in plasma CRP
Nutrition Research Reviews

Table 5. Effect of conjugated linoleic acid (CLA) on inflammation and other immune indices in human subjects

Reference Form of CLA Number of subjects Design Overall result

Kelley et al. CLA mixture 17 F 9 weeks, 3.9 g CLA/d No significant effects on any immune indices (number of
(2000)(137) circulating white blood cells, granulocytes, mono-
cytes, lymphocytes, and their subsets, lymphocytes
proliferation in response to phytohemagglutinin, and
influenza vaccine, serum influenza antibody titers,
and DTH response)
Risérus et al. CLA mixture or t10,c12-CLA 57 M RCT, 12 weeks, 3.4 g CLA or t10,c12- t10,c12-CLA significantly increased CRP
(2002)(60) CLA per d
Risérus et al. c9,t11-CLA 25 M RCT, 12 weeks, 3 g c9,t11-CLA/d c9,t11-CLA significantly increased a pro-inflammatory
(2004)(78) marker (15-keto-dihydro-PGF2a)
Tricon et al. c9,t11- or t10,c12-CLA 39 – 49 M RCT, cross-over, 8 weeks, 0.59, 1.19 or Both isomers decreased mitogen-induced T lymphocyte
(2004)(134) 2.38 g c9,t11-CLA/d or 0.6, 1.3 or 2.5 g activation. No significant effect on lymphocytes or

Conjugated linoleic acid and health benefits


t10,c12-CLA/d CRP
Smedman et al. CLA mixture 50 M þ F RCT, 12 weeks, 4.2 g CLA/d Significant increase in CRP. No significant change in
(2005)(130) TNFa, TNF receptors or VCAM-1
Desroches Supplemented cows’ diets to produce butter 16 M RCT, cross-over, 4 weeks, 0.24 or 2.5 g No significant effect on CRP
et al. naturally enriched with c9,t11-CLA c9,t11-CLA/d
(2005)(80)
Ramakers et al. c9,t11-CLA or t10,c12-CLA 38 M þ F RCT, 13 weeks, 3 g c9,t11-CLA or No significant change in CRP, IL-6, IL-8 and TNFa
(2005)(135) t10,c12-CLA per d
Song et al. CLA mixture 8 M, 20 F RCT, 12 weeks, 3 g CLA/d Significant decrease in pro-inflammatory cytokines
(2005)(139) TNFa and IL-1b. Significant increase in anti-inflam-
matory cytokine IL-10
Nugent et al. c9,t11- or t10,c12-CLA blends 20 M, 35 F RCT, 8 weeks, 2 g 50:50 CLA/d or 1.8 g Ex vivo: no significant effect on PBMC IL-4 production.
(2005)(138) 80:20 CLA/d In vivo: no significant effect on ICAM-1, PGE2, LTB4
Tricon et al. Supplemented cows’ diets to produce milk 32 M RCT, cross-over, 6 weeks, 0.15 or 1.42 g No significant effect on IL-6, VCAM-1, CRP, E-selectin
(2006)(45) naturally enriched with c9,t11-CLA to make c9,t11-CLA/d
products
Mullen et al. CLA mixture 30 M RCT, 8 weeks, 2.2 g CLA/d No significant change in CRP, IL-6 fibrinogen
(2007)(140)
Steck et al. CLA mixture 13 M, 35 F RCT, 12 weeks, 3.2 or 6.4 g CLA/d 6.4 g CLA significantly increased CRP and IL-6
(2007)(57)
Tholstrup et al. CLA mixture or c9,t11-CLA, added to oil 75 F RCT, 16 weeks, 5.5 g CLA mix/d or 5.5 g CLA mix, compared with c9,t11-CLA, significantly
(2008)(131) c9,t11-CLA/d increased CRP and fibrinogen. PAI-1, VCAM-1,
ICAM-1,MCP-1, IL-6 and TNFa were unaffected
Raff et al. Foods baked with butter synthetically enriched 38 M RCT, 5 weeks, 4.6 g CLA/d No significant effect on inflammatory markers (CRP,
(2008)(103) with CLA mixture PAI-1, FVII-C)
Turpeinen et al. c9,t11-CLA 12 M, 28 F RCT, 12 weeks, 2 g CLA/d Significant effects on 8-iso-PGF2a, 15-keto-dihydro-
(2008)(104) PGF2a, EDN, GM-CSF, IFN-g, TNFa and sneezing
Sofi et al. Sheep’s cheese naturally rich in c9,t11-CLA 6 F, 4 M Cross-over, 10 weeks, 0.25 g c9,t11- Significant decrease in cytokines; IL-6, IL-8 and TNFa.
(2009)(110) CLA/d Significant decrease in platelet aggregation
Zhao et al. CLA mixture 44 M, 36 F (subjects RCT, 8 weeks, 4.5 g CLA/d Significant effects on adiponectin, leptin. No significant
(2009)(71) taking blood pressure effect on ACE activity
medication)
Sluijs et al. c9,t11-CLA manufactured from 167 M, 179 F RCT, 6 months, 4 g CLA/d or placebo No significant effect on CRP
(2010)(62) safflower-seed oil

217
218 T. A. McCrorie et al.

concentrations and other inflammatory markers were

inhibitor; MCP, monocyte chemoattractant protein; FVII-C, factor VII coagulant; EDN, eosinophil-derived neurotoxin; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; ACE, angiotensin-converting
VCAM, circulating vascular adhesion molecule; PBMC, peripheral blood mononuclear cell; ICAM, intercellular adhesion molecule; LT, leucotriene; E-selectin, endothelial leucocyte adhesion molecule; PAI, plasminogen activator
CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; F, female; DTH, delayed-type hypersensitivity; t10,c12, trans-10, cis-12; M, male; RCT, randomised controlled trial; c9,t11, cis-9, trans-11; CRP, C-reactive protein;
No significant effect on urinary markers of airway inflam-
No significant effect on CRP, IL-6, TNF-a or adiponectin
No significant effect on adiponectin, leptin, IL-6, IL-8, IL-
observed. In contrast, a study by Sofi et al.(110) found
that consumption of sheep cheese, naturally rich in CLA
(0.25 g c9,t11-CLA per d), for 10 weeks decreased circulat-

5, IFN-g, TNF-a, PAI-1, MCP-1, HGF, ECP


ing levels of the pro-inflammatory cytokines IL-6, IL-8 and

mation (LTC4-E4 and 9a,11b-PGF2a)


TNFa, compared with consumption of a control cows’
cheese. However, as noted above, this study was small,
poorly controlled and may not have been adequately pow-
ered for the multiple variables measured.
Some studies have investigated other immune effects in
addition to inflammation. A study where the diets of
young women were supplemented with a CLA mixture at
Overall result

3.9 g/d for 9 weeks found that no indices of immune


status were affected (such as the number of circulating leu-
cocytes; granulocytes; monocytes; lymphocytes and their
subsets; lymphocytes proliferation in response to phyto-
haemagglutinin and influenza vaccine; and serum influ-
enza antibody titres)(137). However, the sample size was
RCT, 12 weeks, 4.5 g CLA/d or placebo
Nutrition Research Reviews

RCT, crossover, 8 weeks, 3.5 g CLA/d

small, at seventeen. In a larger study, with fifty-five sub-


jects, Nugent et al.(138) found that either a 50:50 CLA mix-
ture or an 80:20 CLA mixture at about 2 g/d had minimal
effects on lymphocytes and cytokines, and had no
additional benefit on immune function compared with
linoleic acid. CLA supplementation has also been linked
to reduced symptoms of birch pollen allergy(104) and
8 weeks, 4.8 g/d

improved airway hyper-responsiveness in asthmatics(132).


However, a second study in asthmatics found no attenu-
Design

ation of airway inflammation or bronchoconstrictive


response(133).
However, Song et al.(139) found that supplementing
twenty-eight males and females with 3 g CLA 50:50 for 12
Number of subjects

weeks had beneficial effects on immune function as it


decreased pro-inflammatory cytokines (TNFa and IL-1b)
and increased an anti-inflammatory cytokine (IL-10). Fur-
13 M, 13 F

thermore, Tricon et al.(134) found that supplementing


3 M, 3 F
27 M

men with 0.6 to about 2.5 g of either c9,t11-CLA or


enzyme; ECP, eosinophil cationic protein; LTC4-E4, cysteinyl 4-series leukotrienes.

t10,c12-CLA per d decreased mitogen-induced T lympho-


cyte activation dose-dependently (however, lymphocytes
and cytokines were unaffected). Mullen et al.(140) showed
c9,t11-CLA or CLA mixture added to yoghurt

that 2.2 g CLA 50:50 per d for 8 weeks decreased stimulated


peripheral blood mononuclear cell IL-2 secretion, but did
not affect other markers including plasma levels of IL-6,
CRP, fibrinogen or TNFa, in thirty men.
Overall, studies investigating the effect of CLA (both sup-
plements and naturally CLA-enriched products) on
CLA mixture (Tonalin)

CLA mixture (Tonalin)

immune indices and inflammation provide inconsistent


results.
Form of CLA

Conjugated linoleic acid, insulin resistance and diabetes


In addition to the potential anti-atherogenic, anti-obesity
Table 5. Continued

and anti-inflammatory properties of CLA, the effects on dia-


Stickford et al.
MacRedmond

Joseph et al.

betes have also been examined. As previously stated,


(2010)(132)

(2011)(133)
(2011)(63)
Reference

increases in overweight and obesity have been concurrent


et al.

with increases in type 2 diabetes, which is characterised by


insulin resistance and occurs as a result of excess adipose
Nutrition Research Reviews
Table 6. Effect of conjugated linoleic acid (CLA) on insulin resistance in human subjects

Reference Form of CLA Number of subjects Design Overall result


(106)
Noone et al. (2002) CLA mixture or 80:20 18 M, 33 F RCT with OGTT, 8 weeks, No effect on insulin or glucose
c9,t11 and t10,c12-CLA 3 g 50:50 CLA or 80:20 CLA per d
Risérus et al. (2002)(60) CLA mixture or t10,c12-CLA 57 M RCT, 12 weeks, 3.4 g CLA or t10,c12-CLA increased insulin
t10,c12-CLA per d resistance and glycaemia
(78)
Risérus et al. (2004) c9,t11-CLA 25 M RCT, 12 weeks, 3 g c9,t11-CLA/d c9,t11-CLA increased insulin compared
with placebo in obese men
Eyjolfson et al. (2004)(155) CLA mixture 4 M, 12 F RCT, 8 weeks, 4 g CLA/d, OGTT Improvements for insulin resistance,
at 0, 4 and 8 weeks corresponding decrease in fasting insulin,
though large variations in response
Gaullier et al. (2004)(65) CLA mixture 31 M, 149 F RCT with OGTT, 1 year, 3.6 g CLA-NEFA/d No effects on glucose or insulin
or 3.4 g CLA-TAG/d
Moloney et al. (2004)(107) CLA mixture 32 M þ F RCT with EGC, 8 weeks, 3 g CLA/d Negative effect on glucose and insulin in
type 2 diabetics
(66) (65)
Gaullier et al. (2005) CLA mixture 24 M, 110 F Continuation of 2004 study , with OGTT, No effects on glucose or HbA1c. Original
2 years, 3.4 g CLA-TAG/d CLA-TAG group significant increase

Conjugated linoleic acid and health benefits


in insulin between 12 and 24 months,
though authors contend that
not diabetogenic
Naumann et al. (2006)(102) c9,t11- or t10,c12-CLA in a 48 M, 39 F RCT, 13 weeks, 3 g c9,t11-CLA No change in glucose or insulin
dairy drink or t10,c12-CLA per d
Tricon et al. (2006)(45) Supplemented cows’ diets to 32 M RCT, cross-over, 6 weeks, 0.15 No effects on insulin or glucose
produce milk naturally enriched or 1.42 g c9,t11-CLA/d
with c9,t11-CLA to make products
Gaullier et al. (2007)(67) CLA mixture (Clarinol) 93 M þ F RCT with OGTT, 6 months, 3.4 g CLA/d No effects on insulin or glucose
Laso et al. (2007)(68) CLA mixture (Tonalin) added to 33 M, 11 F RCT, 12 weeks, 3 g CLA/d No change in insulin resistance
skimmed milk
Syvertsen et al. (2007)(58) CLA mixture (Clarinol) 18 M, 65 F (of these, RCT, 6 months, 3.4 g CLA/d No effects on insulin resistance in
41 completed main study or subsample
substudy using
euglycaemic
insulin clamp)
Tarnopolsky et al. (2007)(154) CLA mixture 19 M, 20 F RCT with OGTT, with and without No effects on glucose or insulin
resistance training,
6 months, 6 g CLA/d plus 5 g creatine/d
or placebo plus creatine
Raff et al. (2008)(103) Foods baked with butter synthetically 38 M RCT, 5 weeks, 4.6 g CLA/d No effect on insulin or glucose
enriched with CLA mixture
(56)
Raff et al. (2009) CLA mixture or c9,t11-CLA 75 F RCT, 16 weeks, 5.5 g CLA/d or No effect on glucose or insulin, HOMA-IR.
5.5 g c9,t11-CLA/d However, women with the highest waist
(same study as Tholstrup circumference (3rd tertile, 94 – 109 cm)
et al. (2008)(131)) had higher fasting insulin in the CLA-mix
group than in control and
c9,t11groups – post hoc analysis
Turpeinen et al. (2008)(104) c9,t11-CLA 12 M, 28 F RCT, 12 weeks, 2 g CLA/d No significant effect on glucose, insulin,
HOMA-IR or QUICKI
(153)
Ahren et al. (2009) CLA mixture (Clarinol) Younger 12 lean, RCT with EGC, cross-over, No effects in young lean or obese or
10 obese; older 12 weeks, 3 g CLA/d plus older lean adults. Obese older adults
16 lean, 11 obese M 3 g n-3 long-chain PUFA/d estimated insulin resistance was
increased with supplementation
Norris et al. (2009)(70) CLA mixture 35 F RCT, cross-over, 16 weeks, 6.4 g CLA/d No effect on glucose or insulin
Herrmann et al. (2009)(61) c9,t11-CLA or t10,c12-CLA or 34 M RCT, crossover, 4 weeks, 3.4 g CLA/d No significant changes in glucose

219
CLA mixture or HOMA-IR
220 T. A. McCrorie et al.

tissue. A 5% reduction in body weight has been shown to

c9,t11, cis-9, trans-11; t10,c12, trans-10, cis-12; M, male; F, female; RCT, randomised controlled trial; OGTT, oral glucose tolerance test; CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; EGC, hyperinsulinaemic-
No significant changes in glucose, insulin
decrease insulin resistance in overweight and obese sub-

insulin, insulin sensitivity or HOMA-IR

No significant effect on glucose, insulin


No significant effect on glucose, insulin
jects(43,141,142). Therefore the observed modest reductions

No significant effect on HOMA-IR


in body weight with CLA mixtures at 3 g/d may also
No significant effect on glucose,

No significant effect on insulin


improve insulin resistance.
Overall, the results from both animal and in vitro work
are conflicting, with the effects of CLA on insulin resistance
examined in addition to other outcomes (atherogenic and
obesogenic properties). The vast majority of studies have
or HOMA-IR

or HOMA-IR

or glucagon
Overall result

examined the effects of CLA isomer mixtures, though


some results do suggest isomeric differences(143). In a
mouse model, feeding a diet rich in t10,c12-CLA induced
insulin resistance whereas c9,t11-CLA improved lipid
metabolism without impairing insulin action(144) by poss-
ible mediation of the pro-inflammatory state(145). Similarly,
studies with male Zucker diabetic fatty (ZDF) rats feeding
a 50:50 blend of CLA reduced glucose and insulin con-
centrations(146), although the diet with 91% c9,t11-CLA
RCT, 12 weeks, 4.5 g CLA/d
Nutrition Research Reviews

RCT, 8 weeks, 4.5 g CLA/d

showed no effect(147). In contrast, in another mouse


RCT, 6 months, 4 g CLA/d
RCT, 7 months, 3 g CLA/d

RCT, crossover, 8 weeks,

model of diabetes, a blend of CLA isomers induced


RCT with OGTT, 56 d,

marked lipodystrophic insulin resistance and glucose toler-


ance(148,149). In the same strain of young and ageing mice,
1.17 g CLA/d

3.5 g CLA/d
or placebo

or placebo

supplementation with the individual isomers or a CLA


euglycaemic clamp; HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index.

mix demonstrated divergent responses(148,149). Supplemen-


Design

tation, with c9,t11-CLA elicited no effects on indices of


insulin resistance, plasma insulin and glucose, whereas
supplementation with t10,c12-CLA or a CLA mix increased
blood pressure medication)
53 children aged 6 – 10 years

plasma glucose, insulin and homeostasis model assessment


44 M, 36 F (subjects taking

of insulin resistance (HOMA-IR). However, during an intra-


venous glucose tolerance test, mice supplemented with
Number of subjects

c9,t11-CLA eliminated glucose faster than the control,


t10,c12-CLA- or CLA mix-fed mice(150). These data highlight
167 M, 179 F

13 M, 13 F

the importance of not just measuring plasma glucose and


insulin, as true effects may only be apparent when more
27 M
18 F

robust measures of insulin resistance are used.


One group has used a proteomics approach for eliciting
the interactions between CLA isomers and diseases in an
CLA from pasture-fed dairy cattle

animal model(151). Proteomic techniques measure changes


c9, t11-CLA manufactured from

Beef and dairy products rich in


CLA mixture in chocolate milk

in the protein complement of a biological system and


c9,t11-CLA or CLA mixture

enable modelling of biological processes in response to


dietary interventions(150). In a study with apoE mice con-
CLA mixture (Tonalin)
safflower-seed oil

added to yoghurt

suming 7% c9,t11-CLA or t10,c12-CLA or control (linoleic


acid), results suggested that c9,t11-CLA exerted anti-
Form of CLA

CLA mixture

diabetic effects due to altered expression of markers,


whereas t10,c12-CLA asserted pro-diabetic effects(60,78,152).
Overall, this study suggests that c9,t11-CLA potentially
contributes to a less severe inflammatory response or
protection against the development of atherosclerosis.
MacRedmond et al. (2010)(132)

However, conducting a trial in human subjects would be


prohibitively expensive and require a rigorously controlled
Joseph et al. (2011)(63)
Racine et al. (2010)(73)

Brown et al. (2011)(50)


Sluijs et al. (2010)(62)
Zhao et al. (2009)(71)

protocol in order to examine the effects of CLA supple-


Table 6. Continued

mentation on protein structure and function.


Currently the anti-diabetic properties of CLA in human
Reference

subjects (Table 6) cannot be fully determined, as few


studies are undertaken using rigorous measures of insulin
resistance such as the hyperinsulinaemic–euglycaemic
Conjugated linoleic acid and health benefits 221

clamp(107,153) or the oral glucose tolerance

Positive decrease in bone resorption markers


intake of CLA had higher BMD of forearm
test(50,56,58,65 – 67,106,154,155). Indeed the majority of results

No effects on bone resorption or formation


No effects on bone resorption or formation

regression. Subjects with above median

No effects on markers of bone formation

BMC accrual in CLA group significantly


on the anti-diabetic properties of CLA relate to studies

No effects on total BMD, hip BMD or


CLA intake significant predictor (4%)
of Ward’s triangle BMD in multiple
where only fasting plasma or serum glucose or insulin

No significant changes in BMC or


have been measured, are not the main focus of the
study and typically have small sample sizes. Given

less than control group

CLA mixture, 50:50 cis-9, trans-11- and trans-10, cis-12-CLA; M, male; RCT, randomised controlled trial; BMD, bone mineral density; F, female; BMC, bone mineral content; OGTT, oral glucose tolerance test.
these limitations, it is perhaps not surprising that the
overall results show no effects of CLA supplemen-

No change on BMD

No effects on BMD

bone area (cm2)


tation(56,61,62,65 – 67,70,71,104,106,132,154) or consumption of

or resorption

femur BMD
CLA-enriched products(45,63,73,102,103) on glucose and

Overall result
insulin. However, supplementing with a CLA mixture has
shown beneficial effects on insulin resistance in healthy
male subjects(155) and type 2 diabetic subjects(74). In con-
trast, a negative effect on insulin resistance was reported

6 months, 6 g CLA/d plus 5 g creatine/d or placebo plus creatine


in type 2 diabetic patients; however, this may have been

Observational study. Dietary intake of CLA from 3 d diet record


due to the bias in the glucose tolerance between the
supplementation and placebo groups and may not have

Continuation of 2004 study(65), 2 years, 3.4 g CLA-TAG/d


been due to CLA supplementation(144).

RCT, with resistance training, 28 d, 6 g CLA mixture/d


RCT, 1 year, 3.6 g CLA-NEFA/d or 3.4 g CLA-TAG/d
Nutrition Research Reviews

A recent study also found increased insulin resistance in

RCT, with resistance training, 7 weeks, 5 g CLA/d


older obese subjects, but no effects of combined CLA– n-3
supplementation in lean or obese younger subjects or

RCT, with and without resistance training,


older lean subjects(153). Supplementation with the individual
isomers, c9,t11-CLA or t10,c12-CLA increased insulin

RCT with OGTT, 56 d, 1.17 g CLA/d


resistance (þ15%) in obese men with the metabolic
syndrome(60,78), whereas a CLA isomer mixture did not

RCT, 6 months, 3.4 g CLA/d

RCT, 7 months, 3 g CLA/d


affect insulin resistance(60). Furthermore, lipid peroxidation

RCT, 8 weeks, 3 g CLA/d


increased relative to placebo when the individual isomers
were administered, but the differences did not remain
significant when adjusted for changes in lipid per-
oxidation(60,78). The authors of these papers suggest that
irrespective of the CLA isomer, CLA-induced lipid per-
Design

oxidation may mediate insulin resistance. However, further


work is required, particularly studies where the hyper-
Table 7. Effect of conjugated linoleic acid (CLA) on bone health in human subjects

insulinaemic –euglycaemic clamp is utilised(152,156). The

aged 6 – 10 years
Number of subjects

conflicting responses to increased CLA intake in both


118 M and F

human and animal studies do not currently imply compel-


31 M, 149 F

24 M, 110 F

53 children
42 M, 43 F

19 M, 20 F

ling anti-diabetic properties of CLA. Thus, studies should


136 F

be designed that provide rigorous measures of insulin resist-


23 M

60 M

18 F

ance in subjects of varying age groups and weight status(157).


pasture-fed dairy cattle
Beef and dairy products
mixture (Clarinol)
CLA mixture (Tonalin)

mixture (Tonalin)

CLA in chocolate milk

Conjugated linoleic acid and bone health


rich in CLA from

Bone is a complex tissue system whereby the skeleton is


Dietary intake
Form of CLA

continually renewed through the resorption (breakdown)


CLA mixture

CLA mixture

mixture

mixture

of existing bone and the formation of new bone (remodel-


ling). Peak bone mass in humans usually occurs late
CLA
CLA
CLA
CLA

in the second or early in the third decade of life with a


progressive decline in bone mineral density starting in
Tarnopolsky et al. (2007)(154)

the fourth decade of life for both men and women(158).


Brownbill et al. (2005)(173)

Pinkoski et al. (2006)(55)


(175)

Bone modelling (children and young adults) or remodel-


Gaullier et al. (2004)(65)

Gaullier et al. (2005)(66)

Gaullier et al. (2007)(67)

Racine et al. (2010)(73)


Doyle et al. (2005)(174)

(50)
Kreider et al. (2002)

ling (adults) is influenced by many factors including


Brown et al. (2011)

nutritional status, hormones and mechanical loading. One


of the consequences of low bone turnover or remodelling
Reference

is the development of osteoporosis, particularly in white,


postmenopausal women. In the UK, the costs of osteo-
porosis to the National Health Service are estimated at
222 T. A. McCrorie et al.

£2.3 billion per year or £6 million per d, with almost 3 in LBM(55). However, this study did not identify whether
million individuals diagnosed with osteoporosis(159). the increases in LBM were due to increased muscle or
Thus, strategies that attenuate decreases in bone mass are bone mass and whether it was an artifact of the 7-week
of great importance, with much of research focused on resistance training programme. Since there are relatively
Ca, vitamin D, protein and vitamin K intakes(160). However, few human studies (four out of seven studies where
other nutrients, including CLA, have been the focus of bone was not the primary outcome examined), the lack
research due to influences on bone mass and meta- of consistency in protocols, measurement of bone meta-
bolism(18,161 – 163). bolites and small sample sizes hinder a clear conclusion
The majority of work on CLA and bone metabolism has between the effects of CLA and bone.
been conducted using human cells and animal models,
particularly those reflecting postmenopausal women. Sup-
Overall conclusions
plementation studies have demonstrated decreased PGE2
production in rats, but results were dependent on the The overall evidence from the studies examined here
CLA concentration levels(164 – 168). PGE2 is an important demonstrates a lack of definitive and reproducible results,
factor in the regulation of bone metabolism, including particularly in relation to the consumption of naturally
bone formation as well as bone resorption(158). PGE2 enriched CLA products, as the number of published studies
production increases in postmenopausal bone loss due to is low relative to the number on synthetic supplements.
oestrogen deficiency(158). CLA may also stimulate Ca The majority of randomised controlled trials are conducted
Nutrition Research Reviews

absorption, thus making more Ca available for bone with CLA supplements, with varying mixtures of isomers
formation(164,169). Recently, Park et al.(170) reanalysed pre- and dosage levels. However, the evidence from animal
vious studies in mice and showed that extra Ca (0.66%) studies is promising, but extrapolation from animal to
in the diet improved CLA effects on bone mass in male, human studies is difficult due to the differences in the
but not female mice. A recent review concluded that amount of CLA used. For example, in animal studies the
based on the current evidence from in vitro and animal observed benefits of CLA on bone are between 0.1–1%
studies the addition of CLA, overall, improves bone CLA of total weight of diet(173). For men consuming on
strength and density(161). However, the majority of studies average 3.0 kg food and beverages per d, this is equivalent
currently published were conducted using CLA isomer to 3 –30 g CLA/d; for women consuming about 2.2 kg food
mixtures. Only two studies have examined the differences and beverages per d, this equates to 2.2–22 g CLA/d(176).
between the c9,t11 and t10,c12 isomers and found no In addition, given the differences in study protocols, rela-
direct effects on bone, but rather attenuation of parathyroid tively small sample sizes and other methodological issues
hormone concentration(171,172). (including measurement of dietary CLA intakes(8) and accu-
Whilst there are numerous publications examining the rate measurement of body composition), it is not surprising
effects of CLA and bone formation in cell and animal that there is a lack of consensus on what health claims
models, studies in human subjects are lacking (Table 7). could be applicable to CLA, either natural or synthetic
Data from an observational study showed that in postme- products. Current submissions on CLA health claims to
nopausal women dietary intake of CLA was a weak but the European Food Safety Authority (EFSA) include seven
significant predictor of Ward’s triangle bone mineral for body weight/LBM, two on immune function, two on
density(173). The same study also found that subjects with antioxidant properties and one relating to insulin. The pre-
above median intake of CLA had higher bone mineral sent review suggests that the only possible candidate
density of the forearm. In contrast, supplementation with would be in relation to the synthetic t10,c12-CLA isomer
a CLA mix (3.0 –3.4 g/d) did not affect bone formation or and reductions in body fat.
resorption in healthy lean, overweight, obese men and
women(65 – 67,174). A further two studies in young and
elderly subjects who completed resistance training in Acknowledgements
addition to CLA supplementation (6 g/d) also demonstrated The present review was prepared as part of a project
no change in bone mineral density and bone mass(154,175). funded by Scottish Enterprise (Glasgow, UK). Nino Binns
Brown et al.(50) reported no change in bone mineral Consulting provides consultancy in nutrition and food
content when subjects consumed a CLA-enriched diet, regulation to a variety of commercial clients.
although the study duration was only 56 d, an insufficient T. A. M. and E. M. K. drafted the review. J. M. W. W., N. B.
length of time for observing changes in bone mineral and M. B. E. L. commented on the review.
content. In children, significantly less bone mineral content There are no conflicts of interest.
accretion occurred in the CLA supplemented after 7
months(73); however, the reasons are not fully elucidated.
Currently, the only human study to demonstrate a positive References
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